Inhibiting Histone Methyltransferase G9a by Addition of Small Molecules

Mentors: Drew Adams & Qiu Wang

G9a is a histone methyltransferase that affects DNA packaging and the regulation of transcription. Several types of cancer have been shown to over-express G9a in cells; therefore drugs that inhibit G9a may be effective cancer treatments. One compound, BIX-01294, has been shown to inhibit G9a and lower histone methylation levels, however, this compound also increases levels of cholesterol in cells.

Jordan and his mentors sought to identify new G9a inhibitors from a collection of small molecules that were previously found to bind to G9a protein. Jordan used an in vitro DELFIA assay to test these compounds for their abilities to inhibit G9a, and he discovered one compound, BRD-X, that was a G9a inhibitor. Jordan then investigated whether BRD-X affected expression of cholesterol biosynthesis genes and cellular cholesterol levels. Whereas BIX-01294 showed increased expression of cholesterol biosynthesis genes and increased levels of cholesterol in cells, BRD-X did not show these effects, and thus may be a promising candidate for a specific G9a inhibitor.

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Jordan, a senior at Winthrop High School, investigated which small molecule binders of the histone methyltransferase G9a are potent inhibitors of G9a activity.